Neuromodulators and Circadian Clocks: Roles in Retinal Function and Dysfunction

神经调节剂和昼夜节律时钟:在视网膜功能和功能障碍中的作用

基本信息

  • 批准号:
    8578402
  • 负责人:
  • 金额:
    $ 39万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1983
  • 资助国家:
    美国
  • 起止时间:
    1983-07-01 至 2014-08-31
  • 项目状态:
    已结题

项目摘要

Project Summary / Abstract Circadian clocks generate daily biological rhythms that provide adaptive advantage to organisms by allowing them to anticipate and prepare for regular daily changes in their environment. Circadian disruption has been associated with numerous immune, inflammatory, and metabolic disorders, including diabetic retinopathy. The retina contains multiple circadian clocks located in a variety of retinal cell types, including amacrine, ganglion, photoreceptor, and retinal pigment epithelial (RPE) cells, that modulate visual processing and generate a circadian rhythm of protection from photo-oxidative stress. Circadian clocks are transcriptional-translational feedback loops of conserved clock genes and proteins that generate ~24h rhythms. CLOCK and NPAS2 have overlapping roles in the feedback loops and both regulate circadian gene transcription. The relative contributions of CLOCK and NPAS2 to retinal circadian oscillators have not been explored. In addition, the mechanisms whereby diverse retinal clocks are entrained to the light-dark cycle and are synchronized to regulate retinal function are still unclear. Dopamine (DA) is a circadian neuromodulator that optimizes retinal physiology for bright light, high-resolution vision during the daytime. We hypothesize that DA synchronizes circadian clocks expressing NPAS2 and CLOCK in distinct retinal cell types to modulate visual processing and rhythmic protection from photo-oxidative stress. Using established genetic models and novel mouse models in which DA and/or specific clock genes are depleted selectively from the retina by conditional gene disruption, we will examine circadian rhythms of visual function, sensitivity to photo-oxidative stress, and gene expression to provide a more clear understanding of the organization retinal circadian clock networks. Research proposed in this application is designed to test the following three predictions of our hypotheses: (1) DA modulates circadian rhythms of contrast sensitivity via dopamine D4 receptor (D4R)-mediated regulation of cAMP signaling and circadian oscillators that drive rhythms with both CLOCK/BMAL1 and NPAS2/BMAL1 complexes. (2) Circadian rhythms of photopic ERG amplitudes are modulated by DA effects on photoreceptors via D4Rs, cAMP, and oscillators that utilize CLOCK but not NPAS2. (3) DA protects photoreceptors against photo-oxidative stress via D4Rs on photoreceptors and via dopamine D5 receptors (D5Rs) and dopamine D2-like receptors on RPE cells by modulating a CLOCK-dependent circadian rhythm of susceptibility to light damage. These innovative studies will elucidate mechanisms of retinal circadian physiology that control high-resolution vision and sensitivity to photo-oxidative stress. They will provide novel insights into ways to improve visual function at night (e.g., shift workers, pilots) and to prevent or treat retinal degenerative diseases.
项目总结/摘要 生物钟产生每日的生物节律,通过允许生物体 他们预测和准备在他们的环境中的日常变化。昼夜节律紊乱 与许多免疫、炎症和代谢紊乱相关,包括糖尿病视网膜病变。的 视网膜包含位于多种视网膜细胞类型中的多个昼夜节律钟,所述视网膜细胞类型包括无长突细胞,神经节细胞, 光感受器和视网膜色素上皮(RPE)细胞,它们调节视觉处理并产生一种 保护免受光氧化应激的昼夜节律。生物钟是转录-翻译的 保守的时钟基因和蛋白质的反馈回路产生~ 24小时的节律。CLOCK和NPAS 2具有 在反馈回路中的作用重叠,两者都调节昼夜基因转录。的相对 CLOCK和NPAS 2对视网膜昼夜节律振荡器的贡献尚未被探索。此外该 不同的视网膜时钟被带入明暗周期并同步的机制, 调节视网膜功能仍不清楚。多巴胺(DA)是一种昼夜神经调节剂, 生理学对于白天明亮的光线,高分辨率的视觉。我们假设DA 在不同的视网膜细胞类型中表达NPAS 2和CLOCK以调节视觉处理的昼夜节律钟, 节奏保护免受光氧化应激。使用已建立的遗传模型和新的小鼠模型, 所述DA和/或特异性时钟基因通过条件性基因破坏从视网膜选择性地耗尽, 我们将研究视觉功能的昼夜节律、对光氧化应激的敏感性和基因表达 以提供对视网膜生物钟网络的组织的更清楚的理解。 本申请中提出的研究旨在测试我们假设的以下三个预测: (1)DA通过多巴胺D4受体(D4 R)调节对比敏感度的昼夜节律 调节cAMP信号传导和昼夜节律振荡器,驱动CLOCK/BMAL 1和 NPAS 2/BMAL 1复合物。 (2)明视ERG振幅的昼夜节律由DA通过D4 Rs对光感受器的作用调节, cAMP和利用CLOCK但不利用NPAS 2的振荡器。 (3)DA通过光感受器上的D4 R和多巴胺保护光感受器对抗光氧化应激 D5受体(D5 Rs)和多巴胺D2样受体通过调节CLOCK依赖性 光损伤易感性的昼夜节律。 这些创新研究将阐明控制高分辨率的视网膜昼夜节律生理机制 视力和对光氧化应激的敏感性。他们将提供新的见解,以改善视觉 夜间功能(例如,轮班工人、飞行员)以及预防或治疗视网膜变性疾病。

项目成果

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P Michael Iuvone其他文献

P Michael Iuvone的其他文献

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{{ truncateString('P Michael Iuvone', 18)}}的其他基金

Regulation of eye development by an Opsin5-dopamine pathway
Opsin5-多巴胺通路调节眼睛发育
  • 批准号:
    9893913
  • 财政年份:
    2017
  • 资助金额:
    $ 39万
  • 项目类别:
Regulation of eye development by an Opsin5-dopamine pathway
Opsin5-多巴胺通路调节眼睛发育
  • 批准号:
    9263420
  • 财政年份:
    2017
  • 资助金额:
    $ 39万
  • 项目类别:
Regulation of eye development by an Opsin5-dopamine pathway
Opsin5-多巴胺通路调节眼睛发育
  • 批准号:
    9461543
  • 财政年份:
    2017
  • 资助金额:
    $ 39万
  • 项目类别:
Neuromodulators and Signaling Cascades in Retina
视网膜中的神经调节剂和信号级联
  • 批准号:
    7001210
  • 财政年份:
    2004
  • 资助金额:
    $ 39万
  • 项目类别:
Neuromodulators and Signaling Cascades in Retina
视网膜中的神经调节剂和信号级联
  • 批准号:
    6838763
  • 财政年份:
    2004
  • 资助金额:
    $ 39万
  • 项目类别:
Neuromodulators and Signaling Cascades in Retina
视网膜中的神经调节剂和信号级联
  • 批准号:
    7171781
  • 财政年份:
    2004
  • 资助金额:
    $ 39万
  • 项目类别:
Neuromodulators and Signaling Cascades in Retina
视网膜中的神经调节剂和信号级联
  • 批准号:
    6724567
  • 财政年份:
    2004
  • 资助金额:
    $ 39万
  • 项目类别:
Properties of AMPA and Kainate receptors
AMPA 和红藻氨酸受体的特性
  • 批准号:
    6873745
  • 财政年份:
    2001
  • 资助金额:
    $ 39万
  • 项目类别:
Properties of AMPA and Kainate receptors
AMPA 和红藻氨酸受体的特性
  • 批准号:
    6727523
  • 财政年份:
    2001
  • 资助金额:
    $ 39万
  • 项目类别:
Properties of AMPA and Kainate receptors
AMPA 和红藻氨酸受体的特性
  • 批准号:
    6539168
  • 财政年份:
    2001
  • 资助金额:
    $ 39万
  • 项目类别:

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